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Proposed causes of Alzheimer disease may abound in the scientific literature, but many focus on a common endpoint: sputtering synapses that spell death for neurons. Several new papers shed molecular light on Aβ’s ill effects at these crucial gaps between two nerve cells. In this week’s PNAS Early Edition, Joachim Herz and colleagues at the University of Texas Southwestern Medical Center, Dallas, show that Reelin signaling through apolipoprotein E (ApoE) receptors may support long-term potentiation (LTP) by counteracting Aβ-induced suppression of N-methyl-D-aspartate (NMDA) receptors. A separate study reports that Aβ also wreaks havoc by binding to neuronal α7 nicotinic acetylcholine (nACh) receptors, and targets this interaction in a potential strategy for relieving Aβ neurotoxicity. That work, led by Hoau-Yan Wang at the City University of New York (CUNY) Medical School, appeared in the September 2 Journal of Neuroscience.

Herz and others have found previously that Reelin, a protein produced by inhibitory interneurons, enhances LTP by binding ApoE receptors (e.g., Weeber et al., 2002). These interactions jumpstart Src family tyrosine kinases, including those that phosphorylate and thereby activate NMDA receptors (Beffert et al., 2005 and ARF related news story). Meanwhile, scientists had discovered that Aβ peptides can set in motion a molecular cascade resulting in the opposite effect on those same NMDA receptors. Through a mechanism that involves binding to α7 nACh receptors, Aβ induces activation of phosphatases that strip tyrosines off NMDA receptors, ramping up receptor endocytosis and weakening LTP (Snyder et al., 2005 and ARF related news story). “You have the phosphatases on one hand, and on the other hand, Reelin is inducing tyrosine kinases that counteract those effects,” Herz said in an interview with ARF. “We have a yin and yang situation.”

Reelin and Aβ—Parallel and Opposing Forces
As a first step to demonstrating this, first author Murat Durakoglugil and colleagues incubated mouse hippocampal slices with Aβ1-42 oligomers and showed that the addition of Reelin into the media could reverse the LTP reduction triggered by Aβ. To confirm that Reelin antagonizes Aβ-induced lowering of NMDA currents by directly increasing NMDA receptor activity, the researchers isolated these receptors in whole-cell recordings from hippocampal neurons. NMDA currents shot up in response to Reelin, dipped upon addition of Aβ25-35 peptides, but held steady when both were present, suggesting that each counteracts the effects of the other. In the normal state, these forces presumably add up to a balanced response to synaptic activity.

To drill deeper into the mechanism behind Reelin’s antagonism of Aβ at the synapse, Herz’s team suppressed NMDA currents in hippocampal neurons by treating them with oligomeric Aβ1-42. In this experiment, Reelin’s ability to rescue these Aβ effects disappeared with the addition of an Src family kinase inhibitor, providing evidence that Reelin counteracts Aβ synaptotoxicity in a manner that relies on intracellular signaling. The Reelin-Aβ counterbalance held under more disease-relevant conditions—that is, when the hippocampal slices were treated with AD brain extracts containing naturally produced Aβ oligomers. Finally, Reelin’s ability to block Aβ-induced LTP reduction faded upon treatment with an NMDA antagonist, suggesting that Reelin’s counteracting effects are mediated by its impact on NMDA but not AMPA receptors.

All told, the data indicate that Reelin and Aβ work against each other by triggering molecular cascades that have opposing effects on NMDA receptors. Extrapolating a model for AD from these pathways, Herz said, “Depending on which one gets the upper hand, you either get the disease or you don’t.”

The findings could eventually bring to light a mechanism by which APOE genotype predisposes certain people to AD. “Since [this work] involves ApoE receptors in the mechanism of Reelin, it raises the possibility that APOE genotype affects the risk of AD at least partially through effects of ApoE on synapses,” Bill Rebeck, Georgetown University, Washington, D.C., wrote in an e-mail to ARF (see full comment below).

The challenge now is to show that the Reelin pathway is differentially impaired by ApoE isoforms. “Does ApoE4, the pathogenic allele, reduce or impair ApoE receptor function in a way that makes the Aβ pathway win?” Herz said. “If we can show that, then I think we will have tied the rationale to the genetics.”

Along similar lines, a paper by Hui Zheng and colleagues at Baylor College of Medicine, Houston, Texas, suggests a functional explanation for how defects in another gene, amyloid precursor protein (APP), could cause trouble for synapses. Analyzing mice with conditional inactivation of APP in presynaptic and postsynaptic compartments, first author Zilai Wang and colleagues propose a trans-synaptic adhesion role for APP and suggest that disturbance of this activity may lead to synaptic dysfunction and AD pathogenesis (Wang et al., 2009). The findings also appear in the September 2 Journal of Neuroscience.

Undoing Damage at Aβ-α7 nAChR Complexes?
Writing in the same issue, the CUNY researchers took a different approach to analyzing Aβ-induced synaptic destruction. Wang and colleagues had shown that Aβ binds with high affinity to neuronal α7 nACh receptors (Wang et al., 2000a; Wang et al., 2000b), leading to intracellular β amyloid buildup and impairment of α7 nAChR channels. These findings, coupled with other research implicating α7 nACh receptors in Aβ-induced harm to NMDA receptors (Snyder et al., 2005), led Wang’s team to ask whether disrupting the Aβ-α7 interaction could revive this lost function.

Given the success of some α7 nAChR-targeting agonists in improving cognition in animal models (Pichat et al., 2007; Beracochea et al., 2008; Marighetto et al., 2008), Wang and colleagues chose one such compound (S 24795) for their studies with synaptosomes prepared from cortex samples of healthy patients and of people with AD.

The researchers speculated that the compound would block future Aβ-α7 interactions, and thereby slow disease progression, if it could someday be offered to AD patients. However, what they really wanted to know was whether the compound would have any effect on neurons already littered with Aβ-α7 complexes—in other words, neurons “already half dead,” Wang said. “Would there be any possibility that we could invigorate those neurons?”

Rather unexpectedly, the answer appeared to be yes. “We showed that the compound can actually kick out some of the β amyloid that may be loosely bound and partially suppressing the function of α7 nACh receptors,” Wang told ARF. Furthermore, the researchers showed that S 24795 increases phosphorylation of NMDA receptor subunits and restores NMDAR function assessed by various measures of calcium influx. This compound, developed by the French pharmaceutical company Servier, has shown promise in preclinical studies (see, e.g., Marighetto et al., 2008) but has not been tested in people.

Putting these data into perspective with those from the study by Herz and colleagues, both imply approaches that should have the same outcome—preservation of a receptor intimately tied to synaptic activity. The studies target Aβ’s synaptotoxic pathway at different levels, though. In Herz’s model, “it’s a competition between Aβ and Reelin,” Wang said. “If Reelin happens to release behind Aβ, then you’re out of luck. The damage is already done. Reelin has to get a head start before Aβ comes in to put a stop on NMDAR activity.” α7 nACh receptors, on the other hand, can be viewed as upstream of NMDA receptors. If one removes the Aβ-α7 interactions, then the NMDA receptor presumably would never receive inhibitory signals, Wang said. Future research will show how this reasoning plays out in dynamic, complex in vivo systems.—Esther Landhuis

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Comment on Herz et al.
This work addresses an exciting target in therapeutic approaches against Alzheimer disease: saving the synapse. Joachim Herz and colleagues recognized that some compounds promote synaptic strength, and have used this knowledge to counteract the negative effects of Aβ on the synapse. Specifically, they have found that Reelin, by signaling through the Src family kinases, prevents Aβ-induced synaptotoxicity. The research brings together an increasing understanding of the effects of Aβ (and Aβ oligomers) on synaptic deficits with growing research into the functions of Reelin on promoting synaptic strength.

There are several interesting aspects to this work. One, since it involves ApoE receptors in the mechanism of Reelin, it raises the possibility that APOE genotype affects the risk of AD at least partially through effects of ApoE on synapses. Two, it identifies non-traditional targets for AD therapeutic approaches, i.e., activation of ApoE receptors and Src family kinases, particularly for pathological processes that occur early in the disease course (loss of synapses). Three, it underscores the idea that Reelin has important functions in the adult brain, and not just during neuronal migration in development.

This research supports some very interesting avenues for research. Does Aβ affect normal functions of ApoE receptors or Src family kinases? Do ApoE isoforms have differential effects on synaptic signaling processes relevant to their risk for AD? Is targeting the molecules identified in their nice model of synaptic dysfunction in AD useful in preventing the progression of AD? It’s a rich area.

The three papers [1-3] discussed in this Research News are highly relevant for the pathogenic mechanisms of Alzheimer disease. They are tied together by their common focus on the synapse, and the way in which APP, or its proteolytic fragment, Aβ, influences synaptic function. Yet, the papers project different views on how synaptic function is perturbed in AD. Two of them [1,2] describe possible ways by which the toxic effects of Aβ on synaptic function could be alleviated. The third paper [3] reports on a novel function of APP in the formation of the synapse, and proposes that this function may be perturbed in AD, causing the synaptic dysfunction that is characteristic for the disease. Thus, the old question of whether AD is the result of the gain of (toxic) function inflicted by the accumulated Aβ, or of the loss of function of APP by abnormal processing, is revived. Most likely, the synaptic pathology that accompanies AD is the result of a combination of gain- and loss-of-function events leading to the disruption of a number of cellular processes downstream from cleavage and intracellular transport of APP. Sooner or later, the enormous amount of research conducted on APP will clarify these molecular and cellular dysregulations.

Unfortunately, APP undergoes a complex cell biology, and may exert its multiple functions both as full-length protein and as cleaved fragments [4]. Thus, there are probably many functions to be lost and many toxic effects to be gained when the metabolism of APP is perturbed, as likely is the case in AD. From the researcher’s point of view, studying APP is both interesting and very challenging. Hopefully, all this exciting research will soon bring some relief to those predisposed to, or suffering from AD.

The results are very interesting and relate closely to findings we obtained in hAPP transgenic mice and humans with AD (1). In our study, we documented a depletion of reelin-positive pyramidal neurons in layer II of the entorhinal cortex in both the experimental models and the human condition. Because efferent projections of these cells could serve as a source of reelin in the hippocampus, we speculated that the depletion of reelin-producing pyramidal neurons in the entorhinal cortex might be associated with decreased reelin levels in the hippocampus, a hypothesis we were able to confirm in hAPP mice. Together with the new findings by Durakoglugil et al., these observations suggest that the Aβ-induced depletion of reelin adds insult to injury, as it would disable the very mechanism the brain could use to counteract the adverse effects of Aβ on synaptic functions.